Calculating Renal Function in Adults

Full update December 2017

―The National Kidney Disease Education Program provides renal function calculators at http://nkdep.nih.gov/lab-evaluation/gfr-calculators.shtml. A GFR calculator app is also available at https://www.kidney.org/apps/app_egfr ―

Introduction

Estimating renal function is necessary when prescribing medications that are renally eliminated. Failure to adjust medication dosing in patients with reduced renal function can lead to increased serum concentrations of the medication and adverse effects. Many classes of medications require dosage modification in patients with impaired renal function. These include many antibiotics, some agents used for diabetes, antihypertensives, and others. This article reviews methods of calculating renal function for the purpose of drug dosing adjustment. The article also discusses recommendations from the National Kidney Disease Education Program (NKDEP) for estimating kidney function for the purpose of medication dosing.

Serum Creatinine

Serum creatinine is often used as a marker of renal function or glomerular filtration rate (GFR). For example, the U.S. prescribing information for Eliquis (apixaban) uses the serum creatinine value along with other characteristics to identify need for a dose reduction in A fib patients.¹ However, the use of serum creatinine alone can be misleading.

Serum creatinine is affected by factors other than GFR including tubular secretion and extra-renal generation and excretion of creatinine. Additionally, the GFR must be significantly impaired before changes in the serum creatinine value are seen.²

There are many non-renal factors that influence serum creatinine. These factors may either increase or decrease serum creatinine, but these alterations do not signify changes in renal function. Patients who have a muscular body typically have high serum creatinine values. As patients age, muscle mass declines, resulting in a reduction in serum creatinine. Similarly, females have lower muscle mass and consequently a lower average serum creatinine. Those who are malnourished or who have undergone amputations also have lower serum creatinine values.²

Diet can also affect serum creatinine values. Cooked meats contain creatinine and can transiently increase serum creatinine levels. Patients who are vegetarians, however, have decreased creatinine generation and therefore lower average serum creatinine levels.²

Finally, medications can influence serum creatinine levels. Trimethoprim and cimetidine can reduce the tubular secretion of creatinine, thereby increasing serum creatinine.² High concentrations of cefotetan and cefoxitin can cause falsely elevated serum creatinine measured with the Jaffe method.^3,4 It is recommended that at least two hours elapse after a cefoxitin dose to draw blood for serum creatinine determination.³

There are several serum creatinine assays in use today. Some variant of the alkaline picrate (Jaffe) method or an enzymatic method is most common. These assay results are reproducible when performed by the same lab using the same equipment. But interlab variation can occur due to differences in equipment used and/or assay manufacturer. Recognition of these problems has led the National Kidney Disease Education Program to develop calibration standards to ensure reported serum creatinine values are more accurate. Assays are now calibrated to a gold standard: isotope dilution mass spectrometry (IDMS). Although serum creatinine measured using the new calibration standards are now more accurate, they are lower than in the past.⁵ Implications for renal dosing will be discussed later in this article.

Creatinine Clearance

Creatinine clearance (CrCl) is often used as an estimate of GFR. The Cockcroft-Gault equation is commonly used to calculate creatinine clearance (mL/min). It was determined using data from men with creatinine clearance of about 30 mL/min to 130 mL/min. This equation factors in age, gender, and weight and is as follows:

CrCl = [(140-age)(weight)]/[(72)(serum creatinine)] multiplied by 0.85 if female

where age is in years, weight is in kg, and serum creatinine is in mg/dL.²

Using International System (SI) units, the equation is:

CrCl = [(140-age)(weight)]/[(serum creatinine)(0.81)] multiplied by 0.85 if female

where age is in years, weight is in kg, and serum creatinine is in umol/L.⁶

An important caveat when using this and other equations is that renal function must be stable for maximum accuracy.²

There is no consensus as to whether the body weight should be adjusted for obesity.⁷ But by convention, the weight used is ideal body weight (IBW), or for obese patients, an adjusted body weight (e.g., adjusted body weight = IBW + 0.4 [actual weight - IBW]).⁵ For women, the result is multiplied by 0.85 to account for reduced muscle mass.

The common practice of substituting a serum creatinine value of 1 mg/dL for elderly patients with serum creatinine <1 mg/dL can underestimate renal function.⁸

There are many other equations used to measure creatinine clearance including the modified Cockcroft-Gault, Jelliffe, Mawer, Gates, Hull, Bjornsson, Salazar-Corcoran, and Davis-Chandler equations. A study of these for estimating creatinine clearance in stable cardiac patients who were awaiting coronary angiography found that the Salazar-Corcoran and Cockcroft-Gault equations were the best for predicting creatinine clearance in the specified population.⁹

Creatinine clearance can also be calculated from a timed (e.g., 24-hour) urine collection.¹⁰ However, timed urine collection is cumbersome, inconvenient, and can be inaccurate due to incomplete urine collection.²

While creatinine clearance is relatively easy to calculate, it is not the same as glomerular filtration rate because creatinine is actively secreted in the proximal tubule as well as filtered by the glomerulus.²

Glomerular Filtration Rate: The MDRD Equation

GFR is the most accurate index of renal function. GFR is affected by age, gender, and body size. In a young adult, the average GFR is approximately 120 to 130 mL/min/1.73 m² and GFR then declines progressively with age.²

GFR cannot be measured directly, but can be calculated by measuring the clearance of an agent that is excreted exclusively by filtration such as inulin, iothalamate, or iohexol. However, use of these markers is impractical in the clinical setting, so serum creatinine values are often used to estimate GFR.²

The National Kidney Foundation, American Society of Nephrology, and National Kidney Disease Education Program recommend the use of serum creatinine to estimate GFR. The abbreviated Modification of Diet in Renal Disease (MDRD) Study equation is one method of estimating GFR. The equation factors in age, gender, and race. (The original MDRD equation also includes albumin levels and serum urea nitrogen.)^2,11 It has been extensively studied and validated and is more accurate than a timed 24-hour urine collection or the Cockcroft-Gault equation for determination of renal function. The MDRD equation for use with the new standardized serum creatinine assay (which all labs should be using now) is:¹²

GFR (mL/min/1.73 m²) = 175 x (SCr) ^-1.154 x (age) ^-0.203 x (0.742 if female) x (1.212 if Black)

where SCr is the serum creatinine concentration in mg/dL, and age is in years. (This equation should not be used to calculate eGFR values >60 mL/min/1.73 m², as discussed below.)¹²

Using SI units (i.e., serum creatinine [SCr] in umol/L), the equation is:¹³

GFR (mL/min/1.73 m²) = 175 x (SCr/88.4) ^-1.154 x (age) ^-0.203 x (0.742 if female) x (1.212 if Black)

While the equation appears cumbersome, it is available on the National Kidney Disease Education Program website at http://nkdep.nih.gov/lab-evaluation/gfr-calculators.shtml. GFR calculator apps can also be found at https://www.kidney.org/apps/ app_egfr.

A study evaluated the accuracy of renal function calculated with the modified MDRD equation in healthy patients vs patients with chronic kidney disease. The authors noted that the development of the MDRD equation did not include healthy individuals so the predictive accuracy in that group is unknown. They found that when compared with the iothalamate clearance test (a test that correlates well with GFR), the MDRD underestimated the GFR in healthy individuals.¹¹ In fact, labs might not report an actual GFR when the estimated GFR is >60 mL/min/1.73 m² because the MDRD loses accuracy at higher GFRs.²

Although the MDRD Study equation is less cumbersome than a timed 24-hour urine collection, there are instances where a 24-hour collection may be necessary for an accurate assessment of renal function. Examples of these include:²

• Extremes of age; MDRD has not been validated in patients over 85 years
  
• Severe malnutrition or obesity
  
• Paraplegia/quadriplegia or other skeletal muscle disease
  
• Vegetarian diet
  
• Rapidly changing renal function
  
• Pregnancy
  
• Patients with estimated GFR >60 mL/min/1.73 m² with need for accurate clearance measure (e.g., donating kidney; need for highly toxic, renally excreted drug [e.g., high-dose methotrexate]).
  

Glomerular Filtration Rate: The CKD-EPI Equation

In 2009, Levy and colleague published a new equation to estimate glomerular filtration rate. This equation, the Chronic Kidney Disease Epidemiology Collaboration equation, or CKD-EPI, was developed because of concerns about the MDRD equation at higher renal function levels. The goal of the development of this equation was to be as accurate at estimating renal function as the MDRD equation at GFR <60 mL/min/1.73 m² yet be more accurate in those patients with a GFR >60 mL/min/1.73 m².¹⁴

The CKD-EPI was evaluated in ten development studies (8,254 patients) and 16 validation studies (3,896 patients) in patients who were 18 years or older.

The CKD-EPI equation is:¹⁵

GFR (mL/min/1.73 m²) = 141 × min (SCr /κ, 1)^a × max(SCr /κ, 1)^-1.209 × 0.993^Age × 1.018 [if female] × 1.159 [if Black]
where:
SCr is serum creatinine in mg/dL,
κ is 0.7 for females and 0.9 for males,
α is -0.329 for females and -0.411 for males,
min indicates the minimum of SCr /κ or 1, and
max indicates the maximum of SCr /κ or 1.

The National Kidney Disease Education Program states that labs that report eGFR numeric values >60 mL/min/1.73 m² should use the CKD-EPI equation because it is more accurate than the MDRD in this range.¹⁶

Implications for Drug Dosing

Laboratories commonly report estimated GFR (eGFR) calculated using the MDRD Study equation when a serum creatinine is ordered. But recommendations for dose adjustment in renal impairment are mainly based on studies using the Cockcroft-Gault equation to estimate renal function. Increasingly, for new medications (e.g., canagliflozin [Invokana] and other SGLT2-inibitors), the MDRD equation is being used in clinical trials to calculate renal function and to provide dosing recommendations.^17,18 The National Kidney Disease Education Program suggests use of either the eGFR or eCrCl for drug dosing.¹⁹ However, using the MDRD or CKD-EPI in place of Cockcroft-Gault can lead to overestimation of dose in up to 50% of patients, particularly the elderly or patients with moderate or severe renal impairment.⁸ The FDA allows manufacturers to base their renal dosing recommendations only on the MDRD or Cockcroft-Gault.²⁰

In one study, the use of the MDRD equation resulted in higher recommended drug dosages in 10% of the study population compared to use of the Cockcroft-Gault equation.²¹ Similarly, other investigators found that use of the MDRD Study equation resulted in overdosing 9.6% of the time, and underdosing 7.3% of the time. Overdosing tended to occur in less severe renal disease.²²

Renal function calculated using the CKD-EPI or MDRD Study equations is standardized to a “normal” body surface area (BSA) and is expressed in mL/min/1.73 m². This allows for a more accurate comparison of a patient’s renal function to normal values since renal function is dependent in part on kidney size. For many drugs, renal dosing recommendations are based on CrCl, which is expressed in mL/min because it is not normalized to BSA. So for purposes of renal dosing of such drugs, for patients who are very large or very small, the eGFR calculated using the MDRD or CKD-EPI (in mL/min/1.73 m²) should be multiplied by the patient’s BSA (m²) to “unadjust.” Unadjusting the eGFR calculated using MDRD or CKD-EPI changes the units to mL/min. BSA can be estimated as follows:

BSA (m²) = square root of: [(height x weight)/3131]

where height is in inches and weight is in pounds.¹⁹

Values will be similar for average-size patients, but they can be very different for very large or very small patients. For example, in an average-size patient with a BSA of 1.75 m², with a MDRD-calculated eGFR of 40 mL/min/1.73 m², the “unadjusted” value will be 40 mL/min:

40 mL/min/1.73 m² x (1.75 m²) = 40 mL/min.

But for a large patient with a BSA of 2.7 m² with an MDRD-calculated eGFR of 40 mL/min/1.73m²:

40 mL/min/1.73 m² x (2.7 m²) = 62 mL/min

A study was conducted comparing Cockcroft-Gault, MDRD, and CKD-EPI in 269 adults with a mean SCr of 1.1 ± 0.4 mg/dL and a mean measured creatinine clearance of 53 ± 13 mL/minute. The MDRD and CKD-EPI values were multiplied by BSA and divided by 1.73 to get units of mL/min. Of the equations, the Cockcroft-Gault equation most closely predicted the CrCl with a value of 49.6 + 14.3 mL/minute. The MDRD and CKD-EPI equations estimated GFR to be 65.5 + 18.5 mL/min and 59.9 + 16.1 mL/minute, respectively. So for medications dosed based on CrCl, the MDRD and CKD-EPI values could have overestimated their doses.⁸

When prescribing drugs with a narrow therapeutic index, or for patients in whom estimates based on creatinine are likely to be inaccurate (e.g. amputation), renal function can be determined using a timed urine collection.^19,23 However, timed urine collection may delay starting treatment.²³ Consider conservative dosing if the drug has a narrow therapeutic index and timed measurement or therapeutic drug monitoring is not feasible.²³

Since 2010, U.S. labs have reported a standardized serum creatinine.² After standardization, most labs’ serum creatinine values decreased by 0.1 to 0.3 mg/dL.² But for many drugs, renal dosing recommendations are based on creatinine clearance calculated using serum creatinine measured using the old, nonstandardized method.⁵ Using the Cockcroft-Gault equation with a serum creatinine measured using the new calibration standards is not likely to affect outcomes regarding renal dose adjustment in most situations.²⁴ “Correcting” serum creatinine to the nonstandardized value is not recommended in clinical practice because any correction factor used is likely to be inaccurate.²³

When calculating renal dosing, keep in mind that renal function estimates are inaccurate when renal function is rapidly changing. eGFR underestimates renal function when serum creatinine is falling.² And if serum creatinine rises 2 to 3 mg/dL in one day, assume glomerular filtration rate is near zero.²

Conclusion

A variety of methods to estimate renal function exist. When assessing renal function in order to adjust medication doses, the eGFR or eCrCl are recommended [Evidence level C; consensus].^19,20 Use the method recommended in the product labeling (including any advice on which weight to use in the Cockcroft-Gault equation) and clinical judgement; do not use the eGFR interchangeably with eCrCl.^8,21-23 No matter which equation is used for renal dosing, it is important to remember that it is only an estimate of renal function; consider the clinical scenario (e.g., patient age, disease severity, rapidly changing renal function) to choose a dose that optimizes benefit and minimizes risk.^19,23,24

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.]

Project Leaders in preparation of this clinical resource (331223): Neeta Bahal O’Mara, Pharm.D., BCPS (Original February 2015); Melanie Cupp, Pharm.D., BCPS (December 2017 update)

References

1. Product information for Eliquis. Pfizer Inc. New York, NY 10017. April 2017.
2. National Kidney Foundation. Frequently asked questions about GFR estimates. https://www.kidney.org/sites/default/files/docs/12-10-4004_abe_faqs_aboutgfrrev1b_singleb.pdf. (Accessed November 8, 2017).
3. Product information for cefoxitin. West-Ward Pharmaceuticals Corp. Eatontown, NJ 07724. May 2017.
4. Product information for cefotetan. Teligent Pharma, Inc. Buena, NJ 08310. December 2015.
5. Wade WE, Spruill WJ. New serum creatinine assay standardization: implications for drug dosing. Ann Pharmacother 2007;41:475-80.
6. Kappel J, Calissi P. Nephrology: 3. Safe drug prescribing for patients with renal insufficiency. CMAJ 2002;166:473-7.
7. Rosborough TK, Shepherd MF, Couch PL. Selecting an equation to estimate glomerular filtration rate for use in renal dosage adjustment of drugs in electronic patient record systems. Pharmacotherapy 2005;25:823-30.
8. Dowling TC, Wang ES, Ferrucci L, Sorkin JD. Glomerular filtration rate equations overestimate creatinine clearance in older individuals enrolled in the Baltimore Longitudinal Study on Aging: impact on renal drug dosing. Pharmacotherapy 2013;33:912-21.
9. Spinler SA, Nawarskas JJ, Boyce EG, et al. Predictive performance of ten equations for estimating creatinine clearance in cardiac patients. Ann Pharmacother 1998;32:1275-83.
10. National Kidney Foundation. KDOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Part 5. Evaluation of laboratory measurements for clinical assessment of kidney disease. Guideline 4. Estimation of GFR. http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/p5_lab_g4.htm. (Accessed November 8, 2017).
11. Rule AD, Larson TS, Bergstralh EJ, et al. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med 2004;141:929-37.
12. National Kidney Disease Education Program. MDRD for adults (conventional units). https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-calculators/mdrd-adults-conventional-units. (Accessed November 8, 2017).
13. National Kidney Disease Education Program. MDRD for adults (SI units). https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-calculators/mdrd-adults-si-units. (Accessed November 8, 2017)
14. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12.
15. National Kidney Disease Education Program. CKD-EPI adults (conventional units). https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-calculators/ckd-epi-adults-conventional-units. (Accessed November 8, 2017).
16. National Kidney Disease Education Program. Estimating GFR. https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate/estimating#the-ckd-epi-equation. (Accessed November 8, 2017).
17. Product information for Invokana. Janssen Pharmaceuticals, Inc. Titusville, NJ 08560. July 2017.
18. Product monograph for Invokana. Janssen Inc. Toronto, ON M3C 1L9. April 2017.
19. National Kidney Disease Education Program. CKD and drug dosing: information for providers. Estimation of kidney function for prescription medication dosage in adults. https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-education-outreach/ckd-drug-dosing-providers. (Accessed November 8, 2017).
20. U.S. Food and Drug Administration. Guidance for industry. Pharmacokinetics in patients with impaired renal function-study design, data analysis, and impact on dosing and labeling. March 2010. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
    Guidances/UCM204959.pdf. (Accessed November 9, 2017).
21. Stevens LA, Nolin TD, Richardson MM, et al. Comparison of drug dosing recommendations based on measured GFR and kidney function estimating equations. Am J Kidney Dis 2009;54:33-42.
22. Moranville MP, Jennings HR. Implications of using modification of diet in renal disease versus Cockcroft-Gault equations for renal dosing adjustments. Am J Health Syst Pharm 2009;66:154-61.
23. Nyman HA, Dowling TC, Hudson JQ, et al. Comparative evaluation of the Cockcroft-Gault equation and modification of diet in renal disease (MDRD) study equation for drug dosing: an opinion of the Nephrology Practice and Research Network of the American College of Clinical Pharmacy. Pharmacotherapy 2011;31;1130-44.
24. Matzke GR, Aronoff GR, Atkinson AJ Jr, et al. Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease Improving Global Outcomes (KDIGO). Kidney Int 2011;80:1122-37.

Cite this document as follows: Clinical Resource, Calculating Renal Function in Adults. Pharmacist’s Letter/Prescriber’s Letter. December 2017.

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